This competitive renewal of our program project in Atherosclerosis continues to represent a mulitdisciplinary approach to understanding the intricate interrelationships of blood- and cell- derived factors with arterial tissue leading to the characteristic pathologic alterations found in atherosclerosis. The objectives of this proposal are to elucidate: 1) how modification of LDL, principally through oxidation, results in enhanced uptake by macrophages and cytotoxicity to proliferating smooth muscle cells and to endothelial cells; 2) how alterations in macrophage function due to interaction with proteins or lipoproteins leads to lipid loading, lipid removal or secretion of inflammatory products; 3) how growth factor production by endothelial cells and macrophages is regulated; 4) how the synthesis of collagen and other proteins by arterial smooth muscle cells in; and 5) how modification of the lipid composition of lipoproteins occurs in the plasma compartments. The rabbit and rat will be used as animal models. Endothelial and smooth muscle cells, derived from rabbit, bovine and human aortas, will be grown in tissue culture. Some techniques to be employed include cell binding of radiolabeled ligands, in vivo infusion of tracers, and colloidal gold-labeled ligands for ultrastructural studies. The research activities supported by Tissue Culture, Morphology, and Lipoprotein Core Facilities. This proposed program is expected to provide new and significant basic information leading to a clearer understanding of the sequence of events in atherogenesis.